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Aryl propionic acid derivative composition and pharmaceutical purpose

A technology of aryl propionic acids and compounds, applied in the field of medicinal chemistry, can solve the problems of lower ulcer rate and adverse reactions

Active Publication Date: 2017-05-10
NANJING HERON PHARMA SCI & TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] After long-term clinical practice, the COX-2-specific inhibitors that were previously regarded as "perfect" have gradually exposed the following problems: (1) the curative effect has not increased, (2) adverse reactions have not decreased; (3) lead to ulcer rate Short-term reduction, no difference in long-term use; (4) Severe myocardial infarction occurs

Method used

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  • Aryl propionic acid derivative composition and pharmaceutical purpose
  • Aryl propionic acid derivative composition and pharmaceutical purpose
  • Aryl propionic acid derivative composition and pharmaceutical purpose

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] The synthesis of embodiment 1 compound a-1

[0081]

[0082] Preparation method using chlorophosphoric acid: Dissolve 25g of the compound of formula II in 70mL of anhydrous acetonitrile, add 13g of diisopropylethylamine, cool down to -5~0°C, slowly add 20mL of anhydrous dichloromethane solution of 12g of chlorophosphoric acid dropwise , after dropping, keep stirring for 1 h, slowly rise to room temperature and stir for 2 h, TLC monitors that the reaction is complete, remove the reaction solvent under reduced pressure, add 150 mL of water and 150 mL of dichloromethane and stir, leave to separate layers, concentrate the dichloromethane layer, and wash the residue with methanol / ethyl acetate recrystallization to obtain 14 g of white solid.

[0083] Among them, the structure of chlorophosphoric acid is Its preparation refers to the synthesis method of "Methyl(S)-4-(chloromethoxyphosphinyl)-3(tert-butyldiphenylsiloxy)butyrate" on page 6 of the specification of patent d...

Embodiment 2

[0086] The synthesis of embodiment 2 compound a-1

[0087] The preparation method using phosphorus oxychloride: dissolve 7.2g of the compound of formula II in 100mL of anhydrous tetrahydrofuran, add 14mL of pyridine, cool down and keep the internal temperature at -10 to -15°C, add dropwise 10mL of phosphorus oxychloride to dissolve in The solution in 30mL of tetrahydrofuran was dropped, stirred at 0-5°C for 1h, removed to room temperature, added 2mL of phosphorus oxychloride, stirred at room temperature until the reaction was complete, and the developer monitored by TLC was ethyl acetate: glacial acetic acid = 10: 1. After the reaction is completed, filter with suction, drop the filtrate into about 600mL of pure water kept at 0-5°C, after the drop is complete, stir at room temperature 25-30°C for 1h, add 300mL of ethyl acetate and stir for 0.5h, let stand to separate layers, The organic phase was washed with pure water and saturated brine, dried over anhydrous sodium sulfate, ...

Embodiment 3

[0090] The synthesis of embodiment 3 compound a-3

[0091]

[0092] The preparation was carried out with reference to the method of Example 1, except that an anhydrous dichloromethane solution of diethyl chlorophosphate was added dropwise.

[0093] Mass Spectrum ESI-MS m / z=385.6, [M+H] + .

[0094] H NMR 1 H-NMR: δppm 7.25(d, 2H), 7.16(d, 2H), 4.04(m, 4H), 3.85(m, 1H), 3.64(m, 1H), 2.74(m, 1H), 2.46(m , 1H), 2.03 (m, 2H), 1.93-1.66 (m, 5H), 1.55 (m, 6H), 1.44 (d, 3H).

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Abstract

The invention discloses an aryl propionic acid derivative composition and a pharmaceutical purpose. Alcohol metabolites of Loxoprofen having highest activity in metabolism is used as a nuclear parent to produce a series of derivatives of phosphate, sulphonate, carbonic ester, and amino-acid ester. The derivatives are used to enhance pesticide effect of anti-inflammatory and analgesic effects, and reduce toxic reaction, and have good pharmacokinetic property. And at the same time, the stimulation of the medicine on the gastrointestinal tract, and medication compliance of patients is improved, and therefore the aryl propionic acid derivative composition is the non-steroidal anti-inflammatory drugs having potentials.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an aryl propionic acid derivative and a pharmaceutically acceptable salt thereof, and an application in the treatment field of non-steroidal anti-inflammatory drugs. Background technique [0002] Loxoprofen Sodium (Loxoprofen Sodium) is an anti-inflammatory and analgesic drug that can inhibit both cyclooxygenase COX-1 and COX-2. As the first non-steroidal anti-inflammatory drug that is the precursor of aryl propionic acid to be synthesized, the curative effect of loxoprofen sodium is mainly manifested in the significant analgesic effect, and the anti-inflammatory and antipyretic effects are comparable to other similar drugs. Clinical trials show that after oral administration, it is metabolized into a trans-OH type drug in the human body, and the concentration distribution in the liver and plasma is higher than that in other parts, and then it is quickly transformed into glucos...

Claims

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Application Information

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IPC IPC(8): C07F9/117C07F9/6574C07C309/65C07C309/67C07C309/69C07D295/088C07C69/96C07C69/157C07C69/24C07C69/614C07C229/08C07C229/36C07C323/58A61K31/661A61K31/665A61K31/255A61K31/495A61K31/265A61K31/222A61K31/216A61K31/223A61P29/00A61P19/02A61P11/00
CPCA61K31/255A61K31/661C07C69/96C07C229/08C07C309/65C07C323/58C07D295/088C07F9/117C07F9/6574C07C69/157C07C69/24C07C69/614C07C229/36C07C309/67C07C309/69
Inventor 叶海晁阳郭彦飞丁伯祥曹卫魏丹闵涛
Owner NANJING HERON PHARMA SCI & TECH CO LTD
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